1 as a Key Determinant of Steroid Hormone Biosynthesis A. Overview of steroidogenesis B. SF-1 and the regulation of steroidogenesis C. Cloning and structural characterization of SF-1 1. Structural features of SF-1 2. Multiple transcripts are encoded by the gene encoding SF-1 3. The gene encoding SF-1 is evolutionarily conserved in vertebrates and invertebrates III. Characterization of Sites of SF-1 Expression and Identification of Its Target Genes A. Profiles of SF-1 expression 1. Adult steroidogenic tissues 2. Embryonic steroidogenic tissues 3. Other sites of SF-1 expression B. Target genes regulated by SF-1 1. Steroidogenic cells 2. Sertoli cells 3. Gonadotropes 4. VMH IV. The Roles Of SF-1 in Vivo: Targeted Gene Disruption to Create SF-1 Knockout Mice A. General features of the SF-1 knockout mice B. Primary steroidogenic tissues in SF-1 knockout mice C. Pituitary and hypothalamic defects in SF-1 knockout mice V. Perspectives and Future Directions A. What are the roles of the various transcripts encoded by the Ftz-F1 gene? B. Does a ligand mediate SF-1 transcriptional activation? C. Where does SF-1 fit within hierarchical cascades of endocrine development? 1. Which other genes also contribute to tissueselective expression of SF-1 target genes? 2. Which target genes of SF-1 mediate its key roles in maintaining the adrenal glands, gonads, and VMH? 3. What mechanisms regulate the expression of SF-1? 4. How is SF-1 related to other genes whose disruptions lead to phenotypes that resemble the SF-1 knockout mice? D. Do other transcription factors/nuclear receptors serve dual roles in development and maintenance of the differentiated phenotype? VI. Conclusion

The orphan nuclear receptor steroidogenic factor 1 (SF-1, also called Ad4BP and officially designated NR5A1) has emerged as an essential regulator of endocrine development and function. Initially identified as a tissue-specific transcriptional regulator of the cytochrome P450 steroid hydroxylases, SF-1 has considerably broader roles, as evidenced from studies in knockout mice lacking SF-1. The SF-1-knockout mice lacked adrenal glands and gonads and therefore died from adrenal insufficiency within the first week after birth. In addition, SF-1 knockout mice exhibited male-to-female sex reversal of their internal and external genitalia, impaired expression of multiple markers of pituitary gonadotropes, and agenesis of the ventromedial hypothalamic nucleus (VMH). These studies delineated essential roles of SF-1 in regulating endocrine differentiation and function at multiple levels, particularly with respect to reproduction. This chapter will review the experiments that established SF-1 as a pivotal, global determinant of endocrine differentiation and function. We next discuss recent insights into the mechanisms controlling the expression and function of SF-1 as well as the current status of research aimed at delineating its roles in specific tissues. Finally, we highlight areas where additional studies are needed to expand our understanding of SF-1 action. I. Initial Isolation of Steroidogenic Factor 1Steroid hormones are essential for fluid and electrolyte balance, intermediary metabolism, sexual differentiation, and reproductive function. Once the pathways of steroid hormone biosynthesis were defined and shown to involve the concerted actions of several cytochrome P450 mixed-function oxidases, attention turned to elucidating the mechanisms that regulate the expression of these enzymes. With the isolation of the bovine 21-hydroxylase cDNA (White et al., 1984b), followed shortly thereafter by the cloning of cDNAs encoding the side-chain cleavage enzyme (Matteson et al., 1984;Morohashi et al., 1984) and 11␤-hydroxylase (John et al., 1984), these questions could be addressed at a molecular level.

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The orphan nuclear receptor steroidogenic factor 1 (SF-1, also called Ad4BP, encoded by the NR5A1 gene) is an essential regulator of endocrine development and function. Initially identified as a tissue-specific transcriptional regulator of cytochrome P450 steroid hydroxylases, studies of both global and tissue-specific knockout mice have demonstrated that SF-1 is required for the development of the adrenal glands, gonads, and ventromedial hypothalamus and for the proper functioning of pituitary gonadotropes. Many genes are transcriptionally regulated by SF-1, and many proteins, in turn, interact with SF-1 and modulate its activity. Whereas mice with heterozygous mutations that disrupt SF-1 function have only subtle abnormalities, humans with heterozygous SF-1 mutations can present with XY sex reversal (i.e. testicular failure), ovarian failure, and occasionally adrenal insufficiency; dysregulation of SF-1 has been linked to diseases such as endometriosis and adrenocortical carcinoma. The current state of knowledge of this important transcription factor will be reviewed with a particular emphasis on the pioneering work on SF-1 by the late Keith Parker.

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